快樂小藥師 Im pharmacist nichts glücklich

PAM，或是你要叫做2-PAM，pralidoxime，這個應該大家都知道，是有機磷的解毒劑，會與Atropine併用。

今天聽到一個案例，就是本來醫師要開Aredia，但是開成PAM，加上護士小姐沒有發現，就把他打進病人體內了。

基本上責任的歸屬不在這邊討論，我們要研究的是，發生這樣的事情，應該怎麼處理呢？

好笑的是，他本身就是解毒劑了，所以要找解毒劑的解毒劑，可能不是這樣容易。

當然，有天真的實習生說：就給他有機磷囉！

千萬不行！！！！你想殺人嗎？

所以我們就從身邊可以找到的文獻開始：

首先，要知道，當藥物發生問題時，第一個要找的資料，就是仿單

是的，就是仿單，看不清楚嗎？

仿單

因為現在很多學名藥的出現，所以對於藥典來說，登載的多半都是原廠提供的資料，並不見得合適妳的狀況，所以做直接而且正確的方式，就是仿單

可是，目前台廠當道，找仿單等於沒找，所以我們就必須動用到資料庫，於是要先知道這個藥物的原開發廠。

由於他是歐洲藥，所以最快可以驗明正身的方式，就是找martindale，於是，提供給大家一個Martindale的摘錄：

Adverse Effects
Use of pralidoxime may be associated with drowsiness, dizziness, disturbances of vision, nausea, tachycardia, headache, hyperventilation, and muscular weakness. Tachycardia, laryngospasm, and muscle rigidity have been attributed to giving pralidoxime intravenously at too rapid a rate. Large doses of pralidoxime may cause transient neuromuscular blockade.

啊啊～～你以為看了副作用就可以了嗎？

還要看藥動資訊

Pharmacokinetics
Pralidoxime is not bound to plasma proteins, does not readily pass into the CNS, and is rapidly excreted in the urine, partly unchanged and partly as a metabolite. The elimination half-life is about 1 to 3 hours.

不過幸好今天發生的這個藥物，是一個解毒劑，而且是使用多年的解毒劑，看他reference的年代就知道了，而且美國和歐洲一樣，都是大量噴灑農藥的地區，所以，美係藥典的資訊應該也會有很多。

首先，要來認識一下化合物的結構

看起來沒有多大的人體傷害性，但是那只是看起來，所以我們要找到化合物的資訊，這時候就需要翻出莫克索引啦

在merck index裡面，可以看到有以下幾種鹽基：

iodide 、Chloride、mesylate

我們用的是Chloride 的，所以看一下他的資訊，你可能會問，那要看啥？分子式？分子量？融點？都不是，是要看毒理學報告：

Toxicity data:  LD50 in rats (mg/kg):  96 i.v. (Fleisher); LD50 in rabbits (mg/kg):  95 i.v.; LD50 in mice (mg/kg):  115 i.v., 205 i.p., 4100 orally (Ellin, Wills)

沒有人類資訊，所以找一下 毒理學的書，可以發現以下幾點：

Acute Toxicity:

i.v.—man TDLo: 14 mg/kg (toxic effects: CNS)

i.v.— rat LD50: 96 mg/kg

i.m.—rat LD50: 150 mg/kg

oral—mouse LD50: 4100 mg/kg

i.p.—mouse LD50: 155 mg/kg

i.v.—mouse LD50: 90 mg/kg

i.m.—mouse LD50: 180 mg/kg

i.v.—rabbit LD50: 95 mg/kg

i.m.—guinea pig LD50: 168 mg/kg

 Overdosage

Manifestations of Overdosage:

Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison.

有沒有發現都沒有micromedex的資料，是的，他很難用，所以晚點再找

Distribution

• Vd: distributed throughout extracellular water
• Protein binding: none

 Metabolism

• Hepatic

 Excretion

• Renal: rapid, partly as metabolite and partly unchanged

 Elimination Half Life

• 74 min to 77 min

 Range of Toxicity

 TOXICITY: Range of toxicity not established. It is difficult to differentiate side effects of the drug from effects of the poison or atropine when used therapeutically. A dose of 14 mg/kg IV was reported to cause CNS toxicity.

算一下，病患現在是打了3Gm，加在500mL裡面，假設體重是50公斤，他的CNS毒性劑量是700mg，跟毒理學的書寫的一樣。

所以，Micromedex等於沒寫，因為有機磷中毒時，給的劑量都是1Gm~2Gm，早就超過了！

不過Micromedex還是給了我們一點希望：

 Elimination Half-life

 接下來，要繼續找AHFS和Drug information handbook

在副作用方面，內容差不多

Adverse Effects 

Although pralidoxime is generally well-tolerated, dizziness, blurred vision, diplopia and impaired accommodation, headache, drowsiness, nausea, tachycardia, hyperventilation, maculopapular rash, and muscular weakness have been reported following administration of the drug. However, it is difficult to differentiate the toxic effects produced by atropine or organophosphates from those of pralidoxime, and the condition of patients suffering from organophosphate intoxication will generally mask minor signs and symptoms reported in normal subjects who receive pralidoxime. When atropine and pralidoxime are used concomitantly, signs of atropinism may occur earlier than when atropine is used alone, especially if the total dose of atropine is large and administration of pralidoxime is delayed. Excitement, confusion, manic behavior, and muscle rigidity have been reported following recovery of consciousness, but these symptoms have also occurred in patients who were not treated with pralidoxime.

Rapid IV injection of pralidoxime has produced tachycardia, laryngospasm, muscle rigidity, and transient neuromuscular blockade; therefore, the drug should be administered slowly, preferably by IV infusion. IV administration of pralidoxime reportedly may also cause hypertension which is related to the dose and rate of infusion. Some clinicians recommend that the patient’s blood pressure be monitored during pralidoxime therapy. For adults, IV administration of 5 mg of phentolamine mesylate reportedly quickly reverses pralidoxime-induced hypertension.

IM administration of pralidoxime may produce mild pain at the injection site.

或是針對各個細項： 

General side effects

Many of the signs and symptoms of organophosphate poisoning are similar to the side effects of pralidoxime. It may be difficult to ascertain which effects are due to the drug and which are toxic symptoms.

Cardiovascular side effects

Cardiovascular side effects have included tachycardia and increased systolic and diastolic blood pressure in normal subjects. Tachycardia has also occurred after excessively rapid infusions. Asystole and cardiac arrest have been reported; however, causality is unclear due to the presence of atropine and an organophosphate insecticide.

Musculoskeletal side effects

Musculoskeletal side effects have included muscle weakness in normal subjects. Laryngospasm and muscle rigidity have occurred after excessively rapid infusions.

Nervous system side effects

Nervous system side effects have included dizziness, headache, and drowsiness in normal subjects.

Respiratory side effects

Respiratory side effects have included hyperventilation in normal subjects.

Ocular side effects

Ocular side effects have included blurry vision, diplopia, and impaired accommodation in normal subjects.

Gastrointestinal side effects

Gastrointestinal side effects have included nausea in normal subjects.

Hepatic side effects

Hepatic side effects in normal subjects have frequently included transient elevations of creatine phosphokinase and occasional increases in AST and ALT, which return to normal within 2 weeks.

Local side effects

Local side effects have included mild to moderate injection side pain within 40 to 60 minutes after intramuscular injection.

再來，是從線上資料庫找到的副作用：

Adverse Reactions

Forty to 60 minutes after intramuscular injection, mild to moderate pain may be experienced at the site of injection.

Pralidoxime may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In patients it is very difficult to differentiate the toxic effects produced by atropine or the organophosphate compounds from those of the drug.

Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers given 1200 mg of Pralidoxime Chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks. Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. A single intramuscular injection of 330 mg in 1 mL in rabbits caused myonecrosis, inflammation and hemorrhage.

When atropine and pralidoxime are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime. 

為何不找injection book呢？因為沒有呀！

看很多，也累了，直接幫大家下一個結論吧

1.PAM中毒或是過量，基本上需要注意CNS副作用及呼吸道監控，如果有需要，請進行插管

2.不專業的說法是，打6隻其實不會有太多嚴重的副作用，但是還是要密切觀察病患的狀況。

3.第一時間的處理建議是稀釋他，就是俗稱的掐水啦，可以用3000以上的NS去輸注。

4.稀釋之後，就是症狀治療了。

5.參考文獻都很舊了，有的甚至比我還老......加減看就好了，直接看病人比較實際。

這件事情除了可以學到PAM之外，還可以順便學到一件事：

Aredia用在化療患者身上，是使用6amp加500mL的Normal saline，run 20mL/hr，至少要 infution超過4hr

其他不及備載的reference：

REFERENCES
1.Landauer, W.: Cholinomimetic tetrogens. V. The effect of oximes and related cholinesterase reactivators, Teratology 15:33 (Feb.) 1977.
2.Moller, K. O., Jenson-Holm, J., and Lausen, H. H.: Ugeskr. Laeg.123:501, 1961.
3.Namba, T., Nolte, C.T., Jackrel, Jr., and Grob, D.: Poisoning due to organophosphate insecticides. Acute and chronic manifestations, Amer. J. Med. 50:475 (Apr.) 1971.
4.Arena, J. M.: Poisoning. Toxicology. Symptoms. Treatments, ed. 4, Springfield, Ill., Charles C.Thomas, 1979, p. 133.
5.Brachfeld, J., and Zavon, M. R.: Organic phosphate (Phosdrin®) intoxication. Report of case and the results of treatment with 2-PAM, Arch. Environ. Health 11:859,1965.
6.Hayes, W. J., Jr.: Toxicology of Pesticides, Baltimore, The Williams & Wilkins Company, 1975, p. 416.
7.AMA Department of Drugs: AMA Drug Evaluations, ed. 4, Chicago, American Medical Association, 1980, p. 1455.

最後回顧一下，我們今天用了哪些參考資料

1.仿單

2.martindale 35

3.Merck index 13

4.Medical toxicology

5.Micromedex

6.AHFS 2009

7.Drug information handbook 16th

8.線上資料庫：Epocrate